Design, synthesis and structure–activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents

Abstract

To continue our efforts toward the development of 99mTc PiB analogs, we have synthesized twenty-four neutral and lipophilic Re (as a surrogate of 99mTc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1–40fibrils. These Re complexes were designed and synthesized via the integrated approach, so their 99mTc analogs would have a greater chance of crossing the blood-brain barrier. While the lipophilicities (logPC18= 1.59–3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki= 30–617 nM) to Aβ1–40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (< 10 nM) will likely be needed. The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current Aβ PET tracers to their 99mTc analogs for more widespread application via the use of SPECT scanners.

Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer's disease

“…Although the binding affinities of these complexes (K i B 30 nM) is inferior to that of most clinical Ab imaging agents (o10 nM) the integrated approach using other Ab binding motifs may prove more successful. 99 The low valent oxidation state of technetium(I) can be stabilized by carbonyl ligands. Pioneering method development has led to the synthesis of fac-[ 99m Tc I (CO) 3 (H 2 O) 3 ] + from [ 99m Tc VII O 4 ] À using sodium boranocarbonate as both reducing agent and an in situ source of carbon monoxide allowing for the convenience of a kit formulation.…”

“…Structure of ML 20 containing benzothiazole based pendant group conjugated to a tridentate chelate; M = Re I ,99 Tc I or 99m Tc I .…”

Recent Advances in the Synthesis and Applications of 2-Arylbenzothiazoles

“…As both these radiolabeled compounds must be prepared directly before use, the short half life of [ 11 C]PIB is a disadvantage and the longer half life of [ 18 F]flutemetamol allows it to be delivered for use at community-based healthcare facilities. Although some bifunctional imaging agents, 6 such as 2-arylbenzothiazole-99m Tc complexes 4 and 5 ( Figure 3) or their Re surrogates have been developed, there is still a long way to go for potential clinical application as amyloid imaging agents due to their only moderate binding affinity (K i ~ 30 nM) to A fibrils. In 2014, Cui and co-workers reported two positively charged 99m Tc/Re-labeled 2-arylbenzothiazole derivatives 6 and 7 (Figure 4) for selectively targeting A plaques.…”

The benzazole scaffold: a SWAT to combat Alzheimer's disease

“…5) have been synthesized using an integrated approach, with the aim of decreasing the molecular weight. 47 They exhibit good to moderate affinity for Ab fibrils in vitro and still have to be tested with 99m Tc in vivo.…”